GLP1-RA: Where Do They Fit In CV Risk Management? Professor John - - PowerPoint PPT Presentation

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GLP1-RA: Where Do They Fit In CV Risk Management? Professor John - - PowerPoint PPT Presentation

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GLP1-RA: Where Do They Fit In CV Risk Management? Professor John Deanfield, UCL ESC Paris: Monday 2 September 2019 Deanfield UCL Professor John Deanfield: Disclosures Received CME honoraria and/or consulting fees from Amgen, Boehringer

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GLP1-RA: Where Do They Fit In CV Risk Management?

Professor John Deanfield, UCL ESC Paris: Monday 2 September 2019

Deanfield  UCL

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Professor John Deanfield: Disclosures

▪ Received CME honoraria and/or consulting fees from

Amgen, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk, Bayer

▪ Research grants from BHF, MRC(UK), NIHR, PHE, MSD,

Pfizer, Aegerion, Colgate, Roche

▪ No conflicts of interest for this presentation ▪ Member of SOUL and SELECT Study Steering Committees

for Novo Nordisk

▪ Board Director of Cydar Ltd

Deanfield  UCL

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Deanfield  UCL

GLP1-RA In CV Risk Management

  • T2DM and CV disease
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Source: Marso SP et al. N Engl J Med 2016;375:311–322 Source: Marso SP et al. N Engl J Med 2016;375:1834–1844

LEADER

Time to first occurrence of CV death, non-fatal MI or non-fatal stroke

6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 5 1 0 1 5 2 0

Patients with event (%)

Placebo Liraglutide

HR: 0.87 (95% CI: 0.78 ; 0.97) p<0.001 for non-inferiority p=0.01 for superiority

Time from randomisation (months)

SUSTAIN 6

Semaglutide Placebo

Patients with event (%)

HR: 0.74 (95% CI: 0.58 ; 0.95) p<0.001 for non-inferiority p=0.02 for superiority

Time from randomisation (weeks)

GLP-1RA CV Outcome Trials

Deanfield  UCL

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Deanfield  UCL

Impact of Diabetes Duration On Outcome In LEADER and SUSTAIN-6

Source: Vermer et al, Diabetes Obes Motab; 2019:21: 1745-1751

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Source: Newman JD, et al, J Am Coll Cardiol 2018; 72(15):1856-69

Diabetes Treatment for CVD Reduction

SGLT-2 Inhibitors GLP-1R Agonists

Deanfield  UCL

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Deanfield  UCL

New Diabetes Drugs: Give together?

Source: Das, S, Everett B et al, J Am Coll Cardiol 2018;72(24):3200-23, 2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease

SGLT-2i

GLP-1RA

  • Complementary actions
  • Good for HbA1c but no CVOT trials
  • Specific patient populations?
  • Guidelines adopting
  • Price will be an issue
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Deanfield  UCL

CVOT Impact on Clinical Guidelines

ADA 2018 recommendation In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, antihyperglycaemic therapy should begin with lifestyle management and metformin and subsequently incorporate an agent proven to reduce major adverse cardiovascular events and cardiovascular mortality (currently, empagliflozin and liraglutide), after considering drug-specific and patient factors (Table 8.1).

Source: Diabetes Care 2018;41(Suppl 1):S73–S85

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Deanfield  UCL

GLP1-RA In CV Risk Management

  • T2DM and CV disease
  • T2DM without clinical CV disease
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REWIND: Primary Outcome

Deanfield  UCL

CV Death, Non-Fatal Myocardial Infarction or Non-fatal Stroke

Source: Lancet. 2019;394:121-130

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Deanfield  UCL

Source: Lingvay I and Leiter LA. Circulation 2018; 137: 2200-2202

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Deanfield  UCL

Liraglutide in Children and Adolescents with T2DM

Source: Tamborlane et al, NEJM DOI/l 10,1056/NEJMoa1903822

Glycated Hemoglobin (mmol/mol) Mean Change from Baseline (%) Fasting Plasma Glucose (mg/dl) Mean Change from Baseline (mmol/l)

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Deanfield  UCL Source: N Engl J Med 2019; 380:2295-2306

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Deanfield  UCL

ACC/AHA: Updated Guidelines for Primary Prevention of CVD

Source: Arnett DK, et al. Circulation 2019; doi: 10.1161/CIR.0000000000000678

March 17 2019 “For adults with T2DM and additional ASCVD risk factors who require glucose lowering therapy despite initial lifestyle modifications and metformin, it may be reasonable to initiate a SGLT2i or a GLP-1RA to improve glycaemic control and reduce CVD risk”

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Deanfield  UCL

GLP1-RA In CV Risk Management

  • T2DM and CV disease
  • T2DM without clinical CV disease
  • Clinical CV disease without T2DM
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Baseline to week 52: J2R-MI data (phase 2)

Change In Body Weight (%)

Change in body weight (%)

Semaglutide 0.05 mg Semaglutide 0.1 mg Semaglutide 0.2 mg Semaglutide 0.3 mg Semaglutide 0.4 mg Placebo pool

Weeks

Liraglutide 3.0 mg

  • 6.0%
  • 8.6%
  • 11.6%
  • 11.2%
  • 13.8%
  • 2.3%
  • 7.8%
  • 15
  • 10
  • 5

2 4 6 8 10 12 14 16 18 20 24 28 32 36 40 44 48 52

Deanfield  UCL Source: O’Neil et al. Presented at: ENDO 2018: Chicago, IL; 17-20 March 2018. Abstract OR12-5

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Deanfield  UCL

SELECT: GLP1-RA in High CVD Risk Non Diabetics

Semaglutide s.c. 2.4 mg once-weekly Placebo s.c. once-weekly Event driven

1225 first MACEs

Randomisation (1:1) N=17,500 patients Male or female ≥45 years of age BMI ≥27

Prior MI Prior stroke PAD

Primary endpoint: Time from randomisation to first occurrence of a composite endpoint consisting of either:

  • CV death
  • Non-fatal myocardial infarction
  • Non-fatal stroke
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Deanfield  UCL

GLP1-RA In CV Risk Management

  • T2DM and CV disease
  • T2DM without clinical CV disease
  • Clinical CV disease without T2DM
  • Barriers To Use
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Deanfield  UCL

GLP1-RA Prescriptions: Partners Health Care System

Source: Vaduganathan,M et al., JACC, 73(12) April 2019:1596-600

7,609 patients aged 61yrs (54% women, 34% CVD)

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Deanfield  UCL

New Oral Formulation of SNAC and Semaglutide

Stomach

Intracellular space

Microvilli

Columnar epithelial cell

Semaglutide SNAC

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Deanfield  UCL

Oral Semaglutide and CV Outcomes in T2DM: PIONEER-6

Source: Husain et al, NEJM DOI: 10.1056/NEJMoa1901118

Composite Primary Outcome: MACE

Percentage of Patients (%) Weeks Since Randomisation

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SOUL – Trial Design

Oral semaglutide 14 mg OD + SoC Placebo + SoC

Up to 5 years (1,225 events)

Trial objective: Demonstrate oral semaglutide lowers risk of MACE compared to placebo

9,462 patients T2D Established CVD or CKD HbA1c 6.5% - 10%

Randomisation (1:1) End of treatment Key endpoints

  • Primary: CV death, non-fatal MI or non-fatal stroke (MACE)
  • Secondary confirmatory: 5-component composite CKD endpoint: CV death, renal death, onset
  • f macroalbuminuria, 50% reduction in eGFR, onset of eGFR < 15 ml/min/1.73m2 or initiation
  • f chronic renal replacement therapy
  • CV Death
  • Composite PAD endpoint: Acute and chronic limb ischemia (MALE)

Deanfield  UCL

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Treatment algorithm in patients with T2DM and ASCVD or high/very high CV risk - drug naïve (1) ESC/EASD guideline 2019

ASCVD, or high / very high CV risk (target organ damage or multiple risk factors)a

a) Type 2 DM - Drug naïve patients SGLT2 inhibitoror GLP-1 RAMonotherapyb Metformin Monotherapy If HbA1cabove target If HbA1cabovetarget AddMetformin If HbA1cabove target

DPP-4i GLP-1 RA SGLT2i if eGFR adequate TZD

+

  • Source: Eur Heart J 2019. https://doi.org/10.1093/eurheartj/ehz486
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Treatment algorithm in patients with T2DM and ASCVD or high/very high CV risk - drug naïve (1) ESC/EASD guideline 2019

ASCVD, or high / very high CV risk (target organ damage or multiple risk factors)a

a) Type 2 DM - Drug naïve patients SGLT2 inhibitoror GLP-1 RAMonotherapyb Metformin Monotherapy If HbA1cabove target If HbA1cabovetarget AddMetformin If HbA1cabove target

DPP-4i GLP-1 RA SGLT2i if eGFR adequate TZD

+

  • Source: Eur Heart J 2019. https://doi.org/10.1093/eurheartj/ehz486

Source: Vaduganathan,M et al., JACC, 73(12) April 2019:1596-600

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Exciting New Era for CVD Management (in DM) Diabetologists Cardiologists Primary Care Nephrology

Deanfield  UCL

  • GLP1-RA’s can reduce the major cause of

morbidity and mortality in patients with Diabetes

  • May also have a role in patients with CVD or

CV risk factors without Diabetes

  • Clinical use vs SGLT2i or in combination

needs further study Could benefit millions of subjects with cardiometabolic risk!